Preparation of normal-alkyl reserpates and alkyl deserpidates



United States PREPARATION OF NORMAL-ALKYL RESERPATES AND ALKYLDESERPIDATES William Irving Taylor, Summit, N. J., assignor to CibaPharmaceutical Products, Inc., Summit, N. 1., a corporafion of NewJersey No Drawing. Application April 9, 1956 Serial No. 576,834

6 Claims. (Cl. 260-287) This invention relates to a process for theproduction of organic compounds and the salts thereof. More particularlythe invention concerns a process for the pro- :duction of compounds ofthe formula:

wherein R represents hydrogen or lower alkyl, R' stands for lower alkyland R" for hydrogen or an acyl radical, and X represents theunsubstituted or substituted remainder of a benzene nucleus, and theirsalts. I

Lower alkyl radicals are for example methyl or ethyl, an acyl'radical ispreferably that of an aliphatic, araliphatic, aromatic or heterocyclicacid, such as lower fatty acids, e. g. acetic or propionic acid, phenylcarboxylic acids, e. g. benzoi'c'* acid or preferably loweralkoxybenzoic acids such as 4-methoxy-benzoic acid,3,4-dimethoxy-benzoic acid, 3,4,5-trimethoxy-benzoic acid, 3,4-methylenedioxy-benzoic acid, cinnamic acids, e. g. methoxy-cinnamicacid, dimethoxy-cinnamic acid or 3,4,5- trimethoxy-cinnamic acid,monocyclic heterocyclic carboxylic acids, e. g. furane-Z-carboxylicacid, thiophene- 2-car boxylic acid or nicotinic acid, or aryl sulfonicacids,

. e. g. toluene sulfonic acids.

It is known that the reduction of synthetically obtainable compounds ofthe formula:

'' wherein R, R and R have the above-mentioned meaning and A stands foran anion such as halogen ion, e. g. E} the chloride ion or a nitrateion, with sodium bo1ohyatent'O L 2,877,225 Patented Mar. 10, 1959 Icedride does not lead to the desired compounds having the3-epi-alloyohimbane configuration like reser'pine, i. e.

v I I have now found that the B-unsaturated compounds of the formula:

wherein X, R,.l{, R" and A have the aforesaid meanings can be reduced toyield the desired compounds hav- 0 ing the 3-epi-alloyohimbaneconfiguration, e. g.

This end can be achieved by liberating the free base of the quaternarystarting material and reducing it with catalytically activated hydrogenunder conditions which do not affect the double bonds in rings A and B.

' Agent's capable of liberating a base from a quaternary salt arealkaline agents, e. g. alkali or earth alkali metal hydroxides such aspotassium or sodium hydroxide or ammonia suchas aqueous ammonia. Thehydrogen used in the reduction step is activated by catalysts containingat least one element selected from the eighth group of the periodicsystem, e. g. platinum or palladium such as 10 percent palladium oncharcoal. The reduction is carried out at room temperature or raisedtemperature, under normal or elevated pressure, preferably it isperformed at an elevated temperature and under pressure.

The starting materials for the process of the invention are compounds ofthe formula:

- t H wherein A, X, R, R, and R" having the aforesaid meaning,preferably compounds of the formula:

OR ll wherein R," R and R" have the aforesaid meaning, R' stands forhydrogen or methoxy and A represents an anion such as a halogen ion, e.g. a chloride ion, or a nitrate ion. Thus, it is, for example, possibleto liberate the free. base of a compound of the formula:.

by treatment with potassium hydroxide and reduce the compound thusobtained with hydrogen in the presence of percent palladium on charcoalso 'as to form the compound of the formula:

tic-a The. starting materials can be. used in the form of theiroptically active antipodes or in the form of the racemates. Depending onthe choice. of the. starting material, the saturated final compound is.la'evo or dextro-rotary or 'racemic. Racemi'c mixtures can be resolvedinto t e optically active antipodes, such as reserpine or deserpidinewhich are laevo-rotary. The final products have valuable sedativeactivity and can be used as medicaments for the treatment of states ofnervousness, anxiety, stress or mental disorders or can be used asintermediates in the production of such pharmacologically activecompounds. The conversion of such intermediates into compounds having asedative activity can be achieved according to known methods which areexemplified on the laevo-rotary compounds in copending applicationSerial No. 526,780, filed August 5, 1955, now Patent No. 2,824,874, byE. Schlittler et al. Thus in the final products being used asintermediates free carboxylic acids can be esterified by treatment withlower diazoalkancs and free hydroxy groups can be esterified, forexample by treatment with acid halides, e. g. chlorides, or anhydrides,esterifiedhydroxyl. groups. can. be hydrolyzed, e. g. by treatment withalkali or alkaline earth hydroxides in lower alkanols, esterifiedhydroxyl groups may be alcoholized, e. g. by treatment with. alkalimetal lower alcoholates, whereby lower carbalkoxy groups aretransesterified. Thus, any of the compounds obtained can be convertedinto a compound having in 16-position a carbomethoxy group and in18-position a trimethoxy hen zoyloxy group, which compounds showsedative activity and can be used as medicaments' for the treatment ofstates of nervousness, anxiety, stress or mental disorders.

The starting materials used in the process of' the invention are knownand can for example be obtained in the following manner: quinone isreacted with 1,4butadiene-l-carboxylic acid in a Diels-Alder addition.The 6,9-dioxo-1,4,5a,6,9,10a-hexahydronaphthalene 1B carboxylic acid ofthe formula:

is then reduced with sodium. borohydride. to 6/8-hydroxy- 9-oxo1,4,5a,6,9,10a hexahydronaphthalene 1/3 carboxylic acid, yielding byoxidation with perbenzoic acid 2,3a-oxido-6 8-hydroxy-9 oxo1,2,3,4,5a,6,9,l0a octahydronaphthalene-lfi-carboxylic acid of theformula:

This compound, after esterification with diazomethane'is subjected to aMeerwein-Ponndorf reduction with aluminum isopropoxide to yield the (l139fx)-lactone of-3,6floxido-9p-hydroxy-3,4,5,6,9,10ahexahydronaphthalenelp-carboxylic acid of theformula:

hydronaphthalene-lfi-carboxylic acid. Oxidation with chromic' acidto'the corresponding 8-oXo-compou'nd, followed by reduction with zinc andacetic acid yields 2alower alkoxy-3p hydroxy-8-oxo-1,2,3,4,5a,8,9,-10aoctahydronaphthalene-lfi-carboxylic acid of the formula:

0R Esterification with diazomethane, acetylation with acetic acidanhydride in pyridine, oxidation with osmium tetroxide and oxidativedegradation with periodic acid gives 20:- loweralkoxy-35-acetoxy-Sfi-aldehydo-fl-carboxymethylcyclohexane-lfl-carboxylic acid methyl ester. This afteresterification with diazomethane is condensed with a tryptamine of theformula:

wherein X has the aforesaid meaning to yield a compound of the formula:

Reduction with sodium borohydride and ring closure with heating resultsin a compound of the formula:

The conversion of an amide thus-obtained into a compound of the formula:

can be achieved by treatment with a ring-closing agent vsuch asphosphorous chloride.

' Salts ofthe products Obtained by the new. process can be made bymethods known per se and are especially acid addition salts, e. g. thoseof the hydrohalic acids, e. g. hydrochloric acid, nitric acid, sulfuricacid, phosphoric acids, perchloric acid, acetic, citric, oxalic,tartaric, ascorbic, methane sulfonic, hydroxyethane sulfonic, p-toluenesulf onic acid or salicylic, p-amino-salicylic acidoracetylsalicylicacid. I

The invention comprises also any process, wherein an intermediateobtainable at any stage ofthe process is used as starting material andthe remaining steps are carried out.

The example which follows is given in the way of illustration and shallnot be construed as a limitation. Many modifications will appear obviousto the man skilled in the art and it is intended that such obviousmodifications are also comprised by my invention. Temperatures are givenin degrees centigrade.

Example 250 mg. of O-acetyl methyl didehydro-reserpate chloride isdissolved in 20 ml. of 50 percent aqueous ethanol and made alkaline bythe addition of 5 ml. of 0.5 N potassium hydroxide. The solution isshaken for two and one-half hours in an atmosphere of hydrogen at 20pounds pressure in the presence of mg. of 10 percent palladium oncharcoal. After removal of the cat alyst the solution is diluted with100 ml. of methylene chloride and washed twice with 50 ml. of water. Themethylene chloride solution is dried over sodium sulfate and the solventevaporated under reduced pressure. Chromatography over activated aluminayields the pure dl-O-acetyl methyl reserpate.

What is claimed is:

1. Process for the manufacture of a member of the group consisting ofcompounds of the formula in which R represents a member of the groupconsisting of hydrogen and methyl, R represents lower alkyl, and R'stands for a member of the group consisting of hydrogen and methoxy, andsalts thereof, which comprises treating a member of the group consistingof compounds of the formula in which R, R and R' have the above-givenmeaning, R" stands for a member of the group consisting of hydrogen, theacyl radical of lower fatty acids, monocyclic aromatic carboxylic acids,monocyclic aryl-lower alkanoic acids, monocyclic heterocyclic carboxylicacids and monocyclic aryl sulfonic acids, and A represents an anion, andsalts thereof, with hydrogen in the presence of a catalyst containing atleast one element selected from the eighth. groupof the periodic systemand in the presence .of an alkaline reagent.

2. Process according to claim 1, wherein A stands for a halogen anion.

with: hydrogen is carried,v out. in the pl' fimaqft' 'kl s siumhyd xid6.- Pr cess according; to c m. 1,, whe e n re tment withhydrogen. iscarried out; in the presence rota, catalyst 3. Process according toclaim 2, wherein A stands for 5 containing palladium a chlorine anion.

4. Process according to claim 1, wherein treatme References Cited in thefile of this patent with hydrogen is carried out in the presence ofanalkali metal hydroxide.

5; Process. according to claim 4, wherein treatme MacPhillamy: Journalof The American Chemical Som m ciety, vol. 77, pages 4335-4343 (August1955).

1. PROCESS FOR THE MANUFACTURE OF A MEMBER OF THE GROUP CONSISTING OFCOMPOUNDS OF THE FORMULA